Synthesis and N-Methyl-d-aspartate (NMDA) Receptor Activity of Ketamine Metabolites
Open accessAbstract
Ketamine is rapidly metabolized in the human body to a variety of metabolites, including the hydroxynorketamines. At least two hydroxynorketamines have significant antidepressant action in rodent models, with limited action against the N-methyl-d-aspartate (NMDA) receptor. The synthesis of 12 hydroxynorketamines and their binding affinity to the NMDA receptor is presented here.
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(2R,6R)-HNK has binding affinity Ki and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons.
“(2R,6R)-HNK has a binding affinity (Ki) and IC50 greater than 100 μM with 24% inhibition at 100 μM, and fails to impact NMDA-evoked currents in CA1 interneurons (Moaddel et al., 2013; Morris et al., 2017; Zanos et al., 2016).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Morris et al., 2017
The NMDA-receptor assay discussion (section labeled Abstract; page unavailable) reports that (2R,6R)-HNK produced 24% inhibition at 100 μM. Our copy does not state the claimed Ki and IC50 values for this compound or report an experiment on NMDA-evoked currents in CA1 interneurons. (LLM, conf=0.85)
Experimental — accuracy not yet measured(2R,6R)-HNK does not displace MK-801 binding to NMDARs at 10 μM.
“its inability to displace MK-801 binding to NMDARs (10 μM).”
From Mechanisms of ketamine and its metabolites as antidepressants (2022) · cites this paper as Morris et al., 2017
The paper’s NMDA-receptor activity discussion reports that (2R,6R)-HNK showed only 24% inhibition of MK-801-site binding at 100 μM, consistent with little activity at clinically relevant concentrations. It does not report the claimed result at 10 μM, so the specific concentration is not verified by our copy. (LLM, conf=0.82)
Experimental — accuracy not yet measured(S)-ketamine has approximately 4-fold greater affinity/potency at inhibiting NMDAR compared to (R)-ketamine.
“(S)-ketamine has ~4-fold greater affinity/potency at inhibiting the NMDAR compared to its (R)-ketamine enantiomer 13, 111–115.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [111]
[3H]-MK-801 binding displacement studies showed affinity of (2R,6R)-HNK to displace MK-801 from NMDAR is >100 μM, and that of (2S,6S)-HNK is 7-20 μM.
“[3H]-MK-801 binding displacement studies showed that the affinity of (2R,6R)-HNK to displace MK-801 from the NMDAR is >100 μM, and that of (2S,6S)-HNK is 7–20 μM 111, 112.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [111]
At relevant concentrations (10 mg/kg or brain Cmax = ~10 μmol/kg in mice), (2R,6R)-HNK does not appear to inhibit the NMDAR.
“Important for the mechanism of action of (2R,6R)-HNK as an antidepressant (and thus ketamine’s action) is the fact that at relevant concentrations (i.e., 10 mg/kg or brain Cmax = ~10 μmol/kg in mice), (2R,6R)-HNK does not appear to inhibit the NMDAR.”
From Mechanisms of ketamine action as an antidepressant (2018) · cites this paper as [111]
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Cites
A randomized trial of an N-methyl-D-aspartate antagonist in treatment-resistant major depression.
Zarate, C. A., Singh, J. B., Carlson, P. J., Brutsche, N. E., Ameli, R., Luckenbaugh, D. A., Charney, D. S., & Manji, H. K. (2006) · Archives of General Psychiatry · doi:10.1001/archpsyc.63.8.856 · Cited by 3,766 · see citing works
Self-citationNMDAR inhibition-independent antidepressant actions of ketamine metabolites
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N. S., et al. (2016) · Nature · doi:10.1038/nature17998 · Cited by 1,609 · see citing works
Self-citationZarate, C. A., Brutsche, N. E., Ibrahim, L., Franco-Chaves, J., Diazgranados, N., Cravchik, A., Selter, J., Marquardt, C. A., Liberty, V., & Luckenbaugh, D. A. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2011.12.010 · Cited by 811 · see citing works
Self-citationKetamine and other NMDA antagonists: early clinical trials and possible mechanisms in depression.
Newport, D. J., Carpenter, L. L., McDonald, W. M., Potash, J. B., Tohen, M., Nemeroff, C. B., & The APA Council of Research Task Force on Novel Biomarkers and Treatments (2015) · American Journal of Psychiatry · doi:10.1176/appi.ajp.2015.15040465 · Cited by 598 · see citing works
Ketamine – More mechanisms of action than just NMDA blockade
SLEIGH, J. W., Harvey, M. G., Voss, L. J., & Denny, B. (2014) · Trends in Anaesthesia and Critical Care · doi:10.1016/j.tacc.2014.03.002 · Cited by 436 · see citing works
Sinner, B., & Graf, B. M. (2008) · Springer eBooks · doi:10.1007/978-3-540-74806-9_15 · Cited by 313 · see citing works
Zarate, C. A., Brutsche, N., Laje, G., Luckenbaugh, D. A., Venkata, S. L. V., Ramamoorthy, A., Moaddel, R., & Wainer, I. W. (2012) · Biological Psychiatry · doi:10.1016/j.biopsych.2012.03.004 · Cited by 282 · see citing works
Self-citationThe use of ketamine as an antidepressant: a systematic review and meta‐analysis
Coyle, C. M., & Laws, K. R. (2015) · Human Psychopharmacology: Clinical and Experimental · doi:10.1002/hup.2475 · Cited by 279 · see citing works
Emerging mechanisms and treatments for depression beyond SSRIs and SNRIs
Dale, E., Bang‐Andersen, B., & Sánchez, C. (2015) · Biochemical Pharmacology · doi:10.1016/j.bcp.2015.03.011 · Cited by 238 · see citing works
Effects of a ketamine metabolite on synaptic NMDAR function
Suzuki, K., Nosyreva, E., Hunt, K. W., Kavalali, E. T., & Monteggia, L. M. (2017) · Nature · doi:10.1038/nature22084 · Cited by 180 · see citing works
Direct Asymmetric Amination of α-Branched Cyclic Ketones Catalyzed by a Chiral Phosphoric Acid
Yang, X., & Toste, F. D. (2015) · Journal of the American Chemical Society · doi:10.1021/jacs.5b00229 · Cited by 179 · see citing works
Moaddel, R., Abdrakhmanova, G., Kozak, J., Jozwiak, K., Toll, L., Jimenez, L., Rosenberg, A., Tran, T., Xiao, Y., Zarate, C. A., et al. (2013) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2012.11.023 · Cited by 176 · see citing works
Self-citationDifferential effects of ketamine enantiomers on NMDA receptor currents in cultured neurons
Zeilhofer, H. U., Swandulla, D., Geißlinger, G., & Brune, K. (1992) · European Journal of Pharmacology · doi:10.1016/0014-2999(92)90248-3 · Cited by 137 · see citing works
Leung, L. Y., & Baillie, T. A. (1986) · Journal of Medicinal Chemistry · doi:10.1021/jm00161a043 · Cited by 135 · see citing works
Moaddel, R., Venkata, S. L. V., Tanga, M. J., Bupp, J. E., Green, C. E., Iyer, L., Furimsky, A., Goldberg, M. E., Torjman, M. C., & Wainer, I. W. (2010) · Talanta · doi:10.1016/j.talanta.2010.08.005 · Cited by 108 · see citing works
Self-citationFerrer-Montiel, A. V., Sun, W. Y., & Montal, M. (1995) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.92.17.8021 · Cited by 45 · see citing works
Zanos, P., Moaddel, R., Morris, P. J., Georgiou, P., Fischell, J. M., Elmer, G. I., Alkondon, M., Yuan, P., Pribut, H. J., Singh, N., et al. (2017) · Nature · doi:10.1038/nature22085 · Cited by 34 · see citing works
Self-citationStereochemical Studies of Demethylated Ketamine Enantiomers
Hong, S. C., & Davisson, J. N. (1982) · Journal of Pharmaceutical Sciences · doi:10.1002/jps.2600710818 · Cited by 24 · see citing works
Amino Ketone Rearrangements. VII.1 Synthesis of 2-Methylamino-2-Substituted Phenylcyclohexanones
Stevens, C. L., Thuillier, A., Taylor, K. G., et al. (1966) · The Journal of Organic Chemistry · doi:10.1021/jo01346a034 · Cited by 19 · see citing works
Synthesis of ketamine metabolites I and II and some anomalous reactions of 6-bromoketamine
Parcell, R. F., & Sanchez, J. P. (1981) · The Journal of Organic Chemistry · doi:10.1021/jo00338a001 · Cited by 19 · see citing works
Biermann, M., Zheng, G., Hojahmat, M., et al. (2015) · Tetrahedron Letters · doi:10.1016/j.tetlet.2015.04.050 · Cited by 13 · see citing works
Berman, F. W., & Murray, T. F. (1996) · Journal of Biochemical and Molecular Toxicology · doi:10.1002/(sici)1522-7146(1996)11:5 · Cited by 2 · see citing works
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- Authors
- Morris, P. J., Moaddel, R., Zanos, P., Moore, C. E., Gould, T., Zarate, C. A., & Thomas, C. J.
- Affiliations
- National Institutes of Health (US)
- University of Maryland, Baltimore (US)
- University of California San Diego (US)
- Corresponding author
- Morris, Patrick J.
- ORCID
- Venue
- Organic Letters
- Publisher
- American Chemical Society (ACS)
- Published
- 2017-08-22
- Volume
- 19
- Issue
- 17
- Pages
- 4572-4575
- ISSN
- 1523-7052 (ISSN-L)
- 1523-7060
- PMC
- PMC5641405
- OpenAlex
- W2749684885
- Cited by
- 83
- References
- 22
- Citations by year
- 2026: 3 · 2025: 9 · 2024: 7 · 2023: 10 · 2022: 13 · 2021: 11 · 2020: 8 · 2019: 10 · 2018: 11 · 2017: 1
- FWCI
- 5.72
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Locations
- Organic Letters (publishedVersion)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- Funders
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology › Treatment of Major Depression
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Neuroscience and Neuropharmacology Research
- Physical Sciences › Chemistry › Organic Chemistry › Chemical synthesis and pharmacological studies
- Keywords
- ketamine metabolites, hydroxynorketamine, NMDA receptor, antidepressant effects
- MeSH terms
- Antidepressive Agents, Ketamine, Molecular Structure, Receptors, N-Methyl-D-Aspartate, N-Methylaspartate
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